TY - JOUR
T1 - Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow
AU - Stern, Javier E.
AU - Son, Sookjin
AU - Biancardi, Vinicia C.
AU - Zheng, Hong
AU - Sharma, Neeru
AU - Patel, Kaushik P.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01 HL112225 and R01 HL090948 to J.E. Stern and NIH grants R56 HL124104 and P01 HL62222 to K.P. Patel.
Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Angiotensin II (AngII) is a key neuropeptide that acting within the brain hypothalamic paraventricular nucleus regulates neurohumoral outflow to the circulation. Moreover, an exacerbated AngII action within the paraventricular nucleus contributes to neurohumoral activation in hypertension. Although AngII effects involve changes in paraventricular nucleus neuronal activity, the precise underlying mechanisms, cellular targets, and distribution of AngII receptors within the paraventricular nucleus remain largely unknown. Thus, whether AngII effects involve direct actions on paraventricular neurons, or whether it acts via intermediary cells, such as astrocytes, is still controversial. To address this important gap in our knowledge, we used a multidisciplinary approach combining patch-clamp electrophysiology in presympathetic paraventricular neurons and astrocytes, along with in vivo sympathetic nerve recordings and astrocyte-targeted gene manipulations. We present evidence for a novel mechanism underlying central AngII actions, which involves astrocytes as major intermediary cellular targets. We found that AngII type 1 receptor mRNA is expressed in paraventricular astrocytes. Moreover, we report that AngII inhibited glutamate transporter function, increasing in turn extracellular glutamate levels. This resulted in the activation of neuronal extrasynaptic NMDA (N-methyl-d-aspartate) receptors, increased presympathetic neuronal activity, enhanced sympathoexcitatory outflow, and increased blood pressure. Together, our studies support astrocytes as critical intermediary cell types mediating brain AngII regulation of the circulation and indicate that AngII-mediated neuronal and sympathoexcitatory effects are dependent on a unique neuroglial signaling modality involving nonsynaptic glutamate transmission.
AB - Angiotensin II (AngII) is a key neuropeptide that acting within the brain hypothalamic paraventricular nucleus regulates neurohumoral outflow to the circulation. Moreover, an exacerbated AngII action within the paraventricular nucleus contributes to neurohumoral activation in hypertension. Although AngII effects involve changes in paraventricular nucleus neuronal activity, the precise underlying mechanisms, cellular targets, and distribution of AngII receptors within the paraventricular nucleus remain largely unknown. Thus, whether AngII effects involve direct actions on paraventricular neurons, or whether it acts via intermediary cells, such as astrocytes, is still controversial. To address this important gap in our knowledge, we used a multidisciplinary approach combining patch-clamp electrophysiology in presympathetic paraventricular neurons and astrocytes, along with in vivo sympathetic nerve recordings and astrocyte-targeted gene manipulations. We present evidence for a novel mechanism underlying central AngII actions, which involves astrocytes as major intermediary cellular targets. We found that AngII type 1 receptor mRNA is expressed in paraventricular astrocytes. Moreover, we report that AngII inhibited glutamate transporter function, increasing in turn extracellular glutamate levels. This resulted in the activation of neuronal extrasynaptic NMDA (N-methyl-d-aspartate) receptors, increased presympathetic neuronal activity, enhanced sympathoexcitatory outflow, and increased blood pressure. Together, our studies support astrocytes as critical intermediary cell types mediating brain AngII regulation of the circulation and indicate that AngII-mediated neuronal and sympathoexcitatory effects are dependent on a unique neuroglial signaling modality involving nonsynaptic glutamate transmission.
KW - angiotensin
KW - astrocyte
KW - blood pressure
KW - heart failure
KW - hypothalamus
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U2 - 10.1161/HYPERTENSIONAHA.116.07747
DO - 10.1161/HYPERTENSIONAHA.116.07747
M3 - Article
C2 - 27698069
AN - SCOPUS:84994896339
SN - 0194-911X
VL - 68
SP - 1483
EP - 1493
JO - Hypertension
JF - Hypertension
IS - 6
ER -